Thiol-type thiamine thionothiolcarbonates

ABSTRACT

Thiol-type thiamine thionothiolcarbonates, i.e. O-(lower)alkoxycarbonyl-S-(substituted or unsubstituted)phenylthiothiocarbonylthiamines, being prepared from S-alkali salts of O-(lower)-alkoxycarbonylthiamines by an interaction with (substituted or unsubstituted)-phenylthiothiocarbonyl groupintroducing agents, or from S-alkali salts of thiamine by an interaction with the (substituted or unsubstituted)phenylthiothiocarbonyl group-introducing agents followed by alkoxycarbonylation of the O-position, possessing antiinflammatory activity and also rapid, prolonged and high level vitamin B1 activity, and being sufficiently stable for various pharmaceutical preparations.

0 United States Patent 1151 3,666,83 1 Takamizawa et al. 51 May 30, 197254] THIOL-TYPE THIAMINE 3,183,232 5/1965 Takamizawa .260/250.5

TI-HONOTHIOLCARBONATES 3,444,167 5/1969 Murakami et al ..260/256.5

[72] Inventors: Akira Takamizawa, Ibaraki-shi; Kentaro FOREIGN PATENTSOR APPLICATIONS Japan 14,388 11 1966 Japan ..260/256.5 [73] Assignee:Shionogi & Co., Ltd., Osaka, Japan Primary ExaminerAlex Mazel [22]Filed: Feb. 17, 1969 [30] Foreign Application Priority Data Mar. 5, 1968Japan ..43/14148 July 11, 1968 Japan ..43/48672 July ll, 1968 Japan..43/48674 [52] U.S. Cl. ..260/256.5 B, 260/649 D, 424/251 [51] Int. Cl...C07d 51/42 [58] Field of Search ..260/256.5 B

[56] References Cited UNITED STATES PATENTS 3,502,674 3/1970 Takamizawaet a1. ..260/256.5

Assistant ExaminerR. J. Gallagher AttorneyWende1-oth, Lind & Ponack [57] ABSTRACT Thiol-type thiamine thionothiolcarbonates, i.e.O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines, being prepared fromS-alkali salts of O-(lower)-alkoxycarbonylthiamines by an interactionwith (substituted or unsubstituted)-phenylthiothiocarbony1group-introducing agents, or from S-alkali salts of thiamine by aninteraction with the (substituted orunsubstituted)-phenylthiothiocarbonyl group-introducing agents followedby alkoxycarbonylation of the O-position, possessing anti-inflammatoryactivity and also rapid, prolonged and high level vitamin B activity,and being sufficiently stable for various pharmaceutical preparations.

11 Claims, No Drawings THlOL-TYPE THIAMINE THIONOTHIOLCARBONATES Thisinvention relates to thioltype thiamine thionothiolcarbonates andproduction thereof. More particularly, the present invention relates toO-(lower)alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines and production thereof.

The said O-(lower)-alkoxyca.rbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines are representable by thefollowing Formula I:

wherein each R and R is independently a member selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy and halogen and R islower alkyl. The compounds represented by the above Formula I showmarked anti-inflammatory activity, even when administered orally, aswell as vitamin B activity, and are useful as medicaments.

Accordingly, a fundamental object of the present invention is to embodynovel thioltype thiamine thionothiolcarbonates and process forpreparation thereof. Another object of the invention is to embodythioltype thiamine thionothiolcarbonates being useful asanti-inflammatory and vitamin B agents, particularly suited to oraladministration. A further object of the invention is to embody thioltypethiamine thionothiolcarbonates having sufficient stability for variouspharmaceutical preparations. A still further object of the invention isto embody pharmaceutical compositions comprising thioltype thiaminethionothiolcarbonates being suited to the treatment of inflammation,edema or vitamin B deficiency. These and other objects of the inventionwill be apparent to those conversant with the art to which the presentinvention pertains from the subsequent descriptions.

The thioltype thiamine thionothiolcarbonates represented by the FormulaI can be prepared in a variety of different ways of which general aspectmay be illustrated by the following scheme:

wherein Py is 2-methyl-4-aminopyrimidin-5-ylmethyl group, M is alkalimetal or alkaline earth metal, and R, R and R each has the samesignificance as designated above.

As illustrative of the objective compounds of the Formula I areO-methoxycarbonyl-S-phenylthiothiocarbonylthiamine,O-ethoxycarbonyl-S-phenylthiothiocarbonylthiamine, O-ethoxycarbonyl-S-(p-tolythio)-thiocarbonylthiamineO-butoxycarbonyl-S-(m-tolylthio)-thiocarbonylthiamine, Oethoxycarbonyl-S-(2,4-xylythio)-thiocarbonylthiamine,O-ethoxycarbonyl-S-(3,5-xylylthio)-thiocarbonylthiamine,O-ethoxycarbonyl-S-(p-methoxyphenylthio)-thiocarbonylthiamine,O-ethoxycarbonyl-S-( o-methoxyphenylthio)-thiocarbonylthiamine,O-ethoxycarbonyl-S-(o-bromophenylthio)- thiocarbonylthiamine,O-butoxycarbonyl-S-(m-bromophenylthio)-thiocarbonylthiarnine,O-ethoxycarbonyl-S-( piodophenylthio)-thiocarbonylthiamine,O-methoxycarbonyl- S-(p-chlorophenylthio)-thiocarbonylthiamine,O-ethoxycarbonyl-S-(2,4-dibromophenylthio)-thioca.rbonylthiamine, O-butoxycarbonyl-S-(3,5-dichlorophenylthio )-thiocarbonylthiamine and thelike.

According to the present invention, the compounds of the Formula I canbe produced by some different methods, which are illustrated in detailbelow, respectively.

I. From an S-alkali salt of O-(lower) :\lkoxycarlmnylthiamine II) TheS-alkali sult of O-(lower)-ulkoxycurbonylthiumine (ll) is usuallyunstable, but can be easily derived from stable compounds, i.e.O-(lower)-alkoxycarbonylthiamine salt (V) andS-(lower)alkoxycarbonylthiamine (VI), by treatment with an alkali suchas sodium hydroxide, potassium hydroxide, calcium hydroxide, sodiumethoxide, potassium ethoxide or the like (cf. Chem. Pharm. Bull., 10,1102 (1962); ibid., 10, 1107 (1962); ibid., l 1, 882 (1963)).

Accordingly, it may be preferred to prepare the starting S- alkali saltof O-(lower)-alkoxycarbonylthiamine (II) from the above mentioned stablecompounds and then subject it to the introduction into the S-position ofthe phenylthiothiocarbonyl group without isolation or purification. Forthis purpose, an O- (lower)-alkoxycarbonylthiamine salt (V) or anS-(lower)-alkoxycarbonylthiamine (V1) is treated with an alkali in asuitable solvent according to a conventional manner. These reactions maybe illustrated by the following scheme:

CH- S 3 \CH9CH20-COOR" SCOOR 3 cHzcHzOH wherein Py, M and R" each hasthe same significance as designated above.

More specifically, for instance, the O-(lower)-alkoxycarbonylthiaminesalt (V) or the S-(lower)-alkoxycarbonylthiamine (VI) is treated with analkali metal alkoxide or an alkaline earth metal alkoxide in a suitableorganic solvent such as a lower alkanol (e.g. methanol, ethanol,propanol), a lower aliphatic ketone (e.g. acetone, methylethylketone), acyclic ether (e.g. tetrahydrofuran, dioxan), a lower alkane nitrile e.g.acetonitrile), a di-(lower)-alkylformamide (e.g. dimethylformarnide),benzene and chloroform. Alternatively, this reaction may be carried outin an aqueous medium with an alkali metal hydroxide or an alkaline earthmetal hydroxide. In either case, the reaction is carried out at a roomtemperature, preferably at 10 to 20 C. Though it is possible to isolateand purify the thus produced S-alkali salt ofO(lower)-alkoxycarbonylthiamine (II), it is usually advantageous toeffect the introduction of a substituted or unsubstitutedphenylthiothiocarbonyl group without isolation or purification asmentioned above. Of course, the introduction of thephenylthiothiocarbonyl group can be effected in the same solvent asemployed in the preparation of the starting compound (II Theintroduction of the phenylthiothiocarbonyl group may be effected with(a) a substituted or unsubstituted phenylthiothiocarbonyl halogenide or(b) a combination of carbon dioxide and a di -(substituted orunsubstituted phenyl)-halonium salt.

When the substituted or unsubstituted phenylthiothiocarbonyl halogenideis employed as the phenylthiothiocarbonyl group-introducing agent, thereaction is eflected at a temperature ranging from about 50 to about 50C, preferably from 30 to C. As mentioned above, the reaction may becarried out in such a solvent as water, a lower alkanol (e.g. methanol,ethanol, propanol), a lower aliphatic ketone (e.g. acetone,methylethylketone), a cyclic ether (e.g. tetrahydrofuran, dioxan), alower alkane nitrile (e.g. acetonltrile), a di-(lower)-allcylfonnamide(e.g. dimethylformamide), benzene, chloroform and the like. Asillustrative of the substituted or unsubstituted phenylthiothiocarbonylhalogenide are phenylthiothiocarbonyl chloride, phenylthiothiocarbonylbromide, phenylthiothiocarbonyl iodide, ptolylthiothiocarbonyl chloride,m-tolylthiothiocarbonyl chloride, o-tolylthiothiocarbonyl chloride, 2,4-xylylthiothiocarbonyl chloride, 3,5-xylylthiothiocarbonyl chloride,p-methoxyphenylthiothiocarbonyl chloride, 0-methoxyphenylthiothiocarbonyl chloride, o-bromophenylthiothiocarbonylchloride, m-bromophenylthiothiocarbonyl chloride,p-iodophenylthiothiocarbonyl chloride, pchlorophenylthiothiocarbonylchloride, 2,4-dichlorophenylthiothiocarbonyl chloride,3,S-dichlorophenylthiothiocarbonyl chloride and the like. Usually, thereaction proceeds very smoothly within few hours, and the product, i.e.O- (lower)-alkoxycarbonyl-S-(substituted or unsubstituted)-phenylthiothiocarbonylthiamine (I), can be isolated and purified by perse conventional procedures such as solvent extraction, chromatography,recrystallization and the like.

On the other hand, when the combination of carbon disul fide anddi-(substituted or unsubstituted phenyl)'halonium salt is employed asthe phenylthiothiocarbonyl group-introducing agent, the introduction ofthe phenylthiothiocarbonyl group is performed in two steps, i.e. thefirst one is an interaction of the starting material (II) with carbondisulfide and the second one is an interaction of the resultingintermediary compound with a di-(substituted or unsubstituted. phenyl)-halonium salt. The intermediary compound produced in the first step maybe represented by the following formula:

wherein Py, M and R each has the same significance as designated above,but isolation of this intermediate is dispensable.

In the first step, the starting S-alkali salt of O-(lower)alkoxycarbonylthiamine (ll) is reacted with carbon disulfide at a temperatureranging from about l0 to about 50 C, preferably around 15 C, in asuitable solvent such as water, a lower alkanol (e.g. methanol, ethanol,propanol), a lower aliphatic ketone e.g. acetone, methylethylketone), acyclic ether e.g. tetrahydrofuran, dioxan), a lower alkane nitrile (e.g.acetonitrile), a di-(lower)-alkyiformamide (e.g. dimethylformamide),benzene, chloroform and the like. The reaction is usually completedwithin several hours, and the above illustrated intermediary compound(II') is afforded. To the thus obtained reaction mixture, there issubsequently added a di- (substituted or unsubstituted phenyl)-haloniumsalt. This second step reaction may be executed at a temperature rangingfrom about 20 to about 50 C, preferably from 0 to 10 C. The reactiontime depends upon the reaction condition, but the reaction is generallycompleted within about 10 hours. The di-( substituted or unsubstitutedphenyl)-halonium salt employed in this step may be represented by thefollowing formula:

wherein X is halogen, Y is inorganic acid residue (e.g. halogen, N01/280 C10 etc), and R and R each has the same significance as designatedabove. This reagent can be prepared by the method described by F. M.Beringer et al (J. Am. Chem. Soc., 75, 2705 (1953)). As illustrative ofthe di- (substituted or unsubstituted phenyl)-halonium salt arediphenyliodonium iodide, diphenyliodonium bromide, diphenyliodoniumsulfate, diphenyliodonium iodate, di-(ptolyl)-iodonium bromide,di-(m-tolyl)- iodonium iodide, di- (2,4-xylyl)-iodonium iodide,di-(3,5-xylyl)-iodonium iodide, di-(p-methoxyphenyl)-iodonium iodide,di-(o-methoxyphenyl)-iodonium iodide, di(o-bromophenyl)-iodonium iodide,di- (p-chlorophenyl)-iodonium iodide, di-(2,4-dichlorophenyl)- iodoniumiodide, di-(3,5-dibromophenyl)-iodonium iodide and the like. Theisolation and purification of the objective compounds (I) can beeffected in per se conventional manners as described above.

2. From an S-alkali salt of thiamine (Ill):

The objective thiol-type thiamine thionothiolcarbonates (I) can also beprepared from an S-alkali salt of thiamine (Ill) by introduction of thephenylthiothiocarbonyl group to the S- position and subsequentalkoxycarbonylation of the O-position. The introduction ofphenylthiothiocarbonyl group into the S-position of the startingmaterial (III) can be executed in the same manner to those for theabove-mentioned phenylthiothiocarbonylation of the other startingmaterial (ll), i.e. with the substituted or unsubstitutedphenylthiothiocarbonyl halogenides or with the combination of carbonyldisulfide and the di-(substituted or unsubstituted phenyl)-haloniumsalts. The thus prepared S-(substituted or unsubstituted)-phenylthiothiocarbonylthiamines (IV) are then subjected to analkoxycarbonylation of the remaining O-position.

The alkoxycarbonylation may be effected with a carbonyl dihalogenide anda lower alkanol. This reaction is usually executed in two steps, i.e.the first one is an interaction of the S- phenylthiothiocarbonylthiamine(IV) with a carbonyl dihalogenide to obtain an intermediaryO-halogenocarbonyl compound (lV') and the second one is an interactionof the intermediary compound (lV') with a lower alkanol. Theintermediary compound (IV'), i.e. O-halogenocarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamine, may be represented by thefollowing formula:

CHO

Py-N

wherein X is halogen, and R, R and Py each has the same significance asdesignated above, but isolation of this intermediary compound is alsodispensable.

in the first step, the S-(substituted or unsubstituted)-phenylthiothiocarbonylthiamine (IV) is reacted with a carbonyldihalogenide (e.g. phosgene, bromophosgene, iodophosgene) in an inertsolvent such as benzene, toluene, ether, tetrahydrofuran, dioxane,chloroform, dichloromethane, trichloroethane, acetone,dimethylformamide, acetonitrile or the like. The reaction proceedsautomatically with generation of heat, and no external heating isrequired. But, if necessary, the reaction mixture may be cooled to keepa moderate reaction velocity.

In the second step, the thus-prepared O-halogenocarbonyl- S-(substitutedor unsubstituted)-pheny1thiothiocarbonylthiamine (IV') is then reactedwith a lower alkanol such as methanol, ethanol, propanol, butanol or thelike. The reaction may be carried out at a temperature ranging fromabout 0 to about 100 C, preferably from to 50 C. As the lower a]- kanolcan play a role of a reaction solvent as well as a reagent, no furthersolvent is requisite. Although the present alkoxycarbonylation has beenabove illustrated step by step, these steps may be effected successivelywithout isolation of the intermediary compound (IV).

The objective produce, i.e. O-(lower)-alkoxycarb0nyl-S- (substituted orunsubstituted)-phenylthiothiocarbonylthiamine (I), may be converted intoan acid addition salt by a per se conventional method. Examples of theacid addition salt include hydrochloride, hydrobromide, hydroiodide,sulfate, nitrate, rhodanate, citrate, oxalate and the like.

The thus-prepared O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines and acid addition slatsthereof are useful as medicaments possessing anti-inflammatory activity,and also rapid, prolonged and high level vitamin B, activity.

Changes in the level of vitamin B, in blood by oral administration ofO-(lower)-alkoxycarbonyl-S-(substituting orunsubstituted)-phenylthiothiocarbonylthiamines were determined inrabbits and the results are shown in the following Table 1, in contrastwith thiamine chloride hydrochloride and thiamine propyl disulfide:

TABLE 1 Vitamin B, Concentration in Blood Vita min B, Concentration(y/dlTest Compound Time (hr) 0 0.5 l 3 5 8 Note: Each (5 mg as thiaminechloride hydrochloride per kg of body weight) of the test compounds wasadministered orally to each test rabbits. At a certain time after oraladministration, vitamin B, concentration in blood was determinedchemically.

Thus, the O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines (I) can be ab sorbed fromthe intestinal canal better than thiamine chloride hydrochloride and theformer can maintain vitamin B, activity for a longer time than thelatter. These characteristic properties are almost equal to those ofthiamine propyl disulfide, which is one of the most excellent and themost frequently used viatmin B, agents.

The O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines (I) possess a highanti-inflammatory activity, and are particularly distinguishable fromthe ever known vitamin B, derivatives having anti-inflammatory activityin the fact that the former are active even when administered orally,whereas the latter are active only when administered orally. Forinstance, edema inhibition activity, abscess inhibition activity andgranulation inhibition activity of theO-(lower)-alkoxyca.rbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines (I), when administeredorally, were examined in rats, and the results are shown in thefollowing Table 2, in contrast with thiamine propyl disulfide:

TABLE 2 Anti-inflammatory Activity Edema Abscess Granulation TestCompound Inhibition Inhibition Inhibition O-Ethoxycarbonyl-S-phenylthiothiocarbonylthiamine 29.7 24 56.9 O-Ethoxycarbonyl-S-(p-toly1thio)-thiocarbonylthiamine 56.6 29.3 38.3 O-Ethoxycarbonyl-S-(3,5-xy1y1thio)- thiocarbonylthiamine 24.9 17.9 30.9 Thiamine propyl di-45.3 13.7 8.8 sulfide (750 mg/kg) Note: 1. The rats were orallypretreated with the test compound mg/kg, unless otherwise specified) andthen the phlogistic agent, 1% carrageenin, is subcutaneouslyadministered. The produced edema was measured and compared with thatproduced without pretreatment. The edema inhibition activity isexpressed as percent inhibition.

2. Abscess was produced by subcutaneous injection of 2% carrageenin inthe sacral region of rats. Then, the test compound (250 mg/kg, totally)was administered orally. One-half of the total dose was administeredimmediately after the injection and the remaining half was administered3 hours later. The rats were sacrificed 24 hours after the injection,and the abscess was dissected and weighed. The abscess inhibitionactivity is expressed as ercent inhibition.

3. Granuloma was produced by embedding carrageenin-soaked filterpupere11et into the lacterovetral region of rats. Then. the testcompound (250 mg/kg, daily) was administered once daily for 6 days.Twenty four hours after the last administration, the rats weresacrificed. and the granulorna dissected and weighed. The granulationinhibition activity is expressed as percent inhibition.

As apparent from the above Table 2, the anti-inflammatory activity ofthe O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines (I) is far superior tothat of the ever known vitamin B, derivative, i.e. thiamine propyldisulfide.

Further, exudation inhibition activity of the O-(1ower)-a1-koxycarbonyl-S-( substituted orunsubstituted)-phenylthiothiocarbonylthiamines (1) was determined inrats, and the results are shown in the following Table 3, in contrastwith a typical and commercially available anti-inflammatory agent,phenylbutazone.

Note: A volume of 20 ml of nitrogen gas was injected subcutaneously intothe back of rats to make a pouch, into the cavity of which 0.5 ml of 10%croton oil was injectedv The administration of the test compound startedon the same day, orally once daily for 10 days. On the 1 1th day. 24hauls afier the last administration, the rats were sacrificed, and thevolume ofthe exudate was measured.

It is clear from the Table 3, the exudation inhibition potencies ofO-ethoxycarbonyl-S-phenylthiothiocarbony1thiamine andO-ethoxycarbonyl-S-(p-tolylthio)-thiocarbonylthiamine are approximately2 3 times that of phenylbutazone.

Likewise, the exudation inhibition potency ofO-ethoxycarbonyl-So(3,5-xylylthio)-thiocarbonylthiamine is almost thesame as that of phenylbutazone.

The acute toxicity of the O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines was investigated in mice,and the median lethal dose values, i.e. LD values, ofO-ethoxycarbonyl-S-phenylthiothiocarbonyl thiamine, O-ethoxycarbonyl-S-(p-tolylthio )-thiocarbonylthiamine andO-ethoxycarbonyl-S-(3,5-xylylthio)-thiocar bonylthiamine were determinedto be more than 800 mg/kg subcutaneously, whereas those of thiaminepropyl disulfide and phenylbutazone were 450 mg/kg and 280 mg/kg,respectively.

Thus, the O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines are remarkable activeanti-inflammatory agents of low toxicity. They are also characterized inthat their anti-inflammatory activity is accompanied with an excellentvitamin B activity. Moreover, the anti-inflammatory agents of thepresent invention are nonsteroidal and thus are free of thedisadvantages of the latter and which are useful, with great advantagevis-a-vis phenylbutazone or thiamine propyl disulfide for example, intreatment of various inflammation conditions in the living body (humanor animal), especially accompanied by vitamin B deficiency.

The O-(lower)-alkoxycarbonyl-S-(substituted orunsubstituted)-phenylthiothiocarbonylthiamines and acid addition saltsthereof are administered in dosage unit form, as carried by a suitablepharmaceutical carrier, to living bodies particularly for the relief ofvarious inflammations and edemata, eg. rheumatism, especiallyaccompanied by vitamin B deficiency. Normally the preparation is orallyadministered, although they are just as effective when otherwiseadministered. They may be administered in various dosages eg 10, 20, 30,50, 100, 150, 200 or 300 milligrams, although the unit dosage range mayvary more broadly from about 5 to 1,000 milligrams and preferably fromto 300 milligrams. It can be added to or otherwise used with variouspharmaceutical carriers. By way of exemplification, various solidcarriers may be employed such as lactose, mannitol, corn starch, talcand magnesium stearate as well as other tableting aids and fillers. Ifdesired, some other ingredients such as prednisolone, dexamethasone,betamethasone, acetylsalicylic acid, chloroquine, aminopyrine,indomethacin, phenylbutazone and the like can be mixed with thepresently provided thiamine thionothiolcarbonates. The medicinalmixtures can then be tableted or encapsulated in a hard gelatinecapsule, depending on the commercial unit form desired. Ordinarily,tableting is preferred. The amount of carrier or diluent may vary,according to tablet size desired or whether the dosage is made up inencapsulated form, from zero to the maximum amount consistent with thepractical limits of bulk for a dosage unit. Normally the carrier withwhich the medicament is mixed does not exceed about 300 to 500milligrams.

Following examples are given as illustration of presentlypreferredembodiments of the invention. It should be understood, however, thatthey are given solely for the purpose of illustration and are not to beconstrued as limitative of this invention, many minor variations ofwhich are possible. In the examples which follow, parts by weight bearthe same relation to parts by volume as do grams to milliliters. Thetemperatures are set forth in degree centigrade. The abbreviations haveconventional significances.

EXAMPLE 1 Preparation of O-Ethoxycarbonyl-S-phenylthiothiocarbonylthiamine Procedure la To a suspension ofS-ethoxycarbonylthiamine (17.7 parts by weight) in anhydrous ethanol(150 parts by volume) is added dropwise a solution of metallic sodium(1.15 parts by weight) in anhydrous ethanol (100 parts by volume) at 10C.

The mixture is warmed to 20 C and allowed to stand at the sametemperature for 5 minutes. To the thus prepared solution of S-sodiumsalt of O-ethoxycarbonylthiamine is added phenylthiothiocarbonylchloride (9.44 parts by weight) at 30 20 C, and the mixture is stirredfor 1.5 hours. Then, the reaction mixture is adjusted to pH 2.0 withethanolic hydrogen chloride and evaporated under reduced pressure. Theresidue is extracted with chloroform, the extract is washed with water,sodium hydrogen carbonate solution and water successively, dried withanhydrous sodium sulfate and evaporated. The residue is crystallized bytreatment with ethyl acetate and recrystallized from ethyl acetate-etherto give 0- ethoxycarbonyl-S-phenylthiothiocarbonylthiamine 2 1 .7 partsby weight), m.p. 161 162 C. Anal. Calcd. for C l-1, 0,, N 5 C, 52.18; H,5.17; N, 11.06; S, 18.98. Found: C, 52.12; H, 5.05; N, 11.02; 5, 18.67.IR vf ff cm: 1746, 1669, 1258, 1042, 1011. Procedure 1bO-Ethoxycarbonylthiamine chloride hydrochloride (21.5 parts by weight)is dissolved in 10 percent aqueous sodium hydroxide solution (60 partsby weight) and the mixture is allowed to stand for 30 minutes underice-cooling. To the thus prepared solution of S-sodium salt ofO-ethoxycarbonylthiamine is added a solution of carbon disulfide (11.4parts by weight) in dimethylformamide (200 parts by volume), and themixture is stirred for 15 minutes under ice-cooling. To the mixture isadded dropwise a solution of diphenyliodonium iodide (22.5 parts byweight) in dimethylformamide (200 parts by volume) at 0 4 C, and themixture is stirred at the same temperature for 7 hours. After dilutionwith water, the mixture is extracted with chloroform, the extract iswashed with water, and dried with anhydrous magnesium sulfate. Afterremoval of the solvent, the residue is purified by silicagelchromatography, and then recrystallized from ethyl acetate-ether to giveO-ethoxycarbonyl-S-phenylthiothiocar' bonylthiamine (18 parts byweight), which is identical with that produced by the procedure 1a.Procedure 2a To a suspension of S-sodium salt of thiol-type thiamine(9.0 parts by weight) in anhydrous ethanol (60 parts by volume) is addeddropwise phcnylthiothiocarbonyl chloride (42 parts by weight) at 17 15C, and the mixture is stirred at the same temperature for 2 hours. Thetemperature is elevated to room temperature, and the precipitates arecollected by filtration. After washing with ice-cooled water, theprecipitates collected are recrystallized from chloroform to giveS-phenylthiothiocarbonylthiamine (8.1 parts by weight), m.p. 91 C. Anal.Calcd. for C, H O N,S C, 52.51; H, 5.10; N, 12.89; S, 22.13. Found: C,48.38; H, 4.99; N, 12.51; S, 21.14.

To a solution of S-phenylthiothiocarbonylthiamine (8.1 parts by weight)in chloroform parts by volume) is added dropwise another solution ofphosgene (2.5 parts by weight) in toluene (5 parts by volume), and theresultant mixture is stirred at room temperature (10 30 C) for 3 hours.After removal of the solvent under reduced pressure, the residue isadded with ethanol (20 parts by volume), and the mixture is heated at 50C for 1 hour. Evaporating under reduced pressure, the residue isextracted with chloroform, the extract is washed with water, sodiumhydrogen carbonate solution and water successively, dried with anhydroussodium sulfate and evaporated. The residue is recrystallized from ethylacetateether to give O-ethoxycarbonyl-S-phenylthiothiocarbonylthiamine(15 parts by weight), which is identical with that produced by theprocedure 1a. Procedure 2b To a suspension of S-sodium salt ofthiol-type thiamine (containing 2 molar equivalents of sodium chloride)(2.25 parts by weight) in dimethylformamide (20 parts by volume) isadded carbon disulfide (1.14 parts by weight), and the mixture isstirred for 10 minutes at 0 4 C. Then, to the mixture is added dropwisea solution of diphenyliodonium iodide (2.18 parts by weight) indimethylforrnamide (20 parts by volume) at 0 -4 C and the mixture isstirred at the same temperature for 4 hours. After dilution with water,the mixture is extracted with chloroform, the extract is washed withwater, dried with anhydrous sodium sulfate, and evaporated. The residueis purified by silica gel chromatography, and then recrystallized fromchloroform to give S-phenylthiothiocarbonylthiamine (1.2 parts byweight), m.p. 90 -91 C, which is identical with that obtained in theprocedure 20.

The intermediary product is subsequently treated with phosgene andethanol in the same manner as described in procedure 2a to giveO-ethoxycarbonyl-S-phenylthiothiocarbonylthiamine (1.0 part by weight),which is identical with that produced by the procedure In.

EXAMPLE 2.

Preparation of O-ethoxycarbonyl-S-(p-tolylthio)- thiocarbonylthiamineProcedure 10 To a suspension of S-ethoxycarbonylthiamine (11.7 parts byweight) in anhydrous ethanol (150 parts by volume) is added dropwise asolution of metallic sodium (0.77 part by weight) in anhydrous ethanol(100 parts by volume) at 30 -20 C. The mixture is wanned to 20 C andallowed to stand at the same temperature for minutes. To the thusprepared solution of S-sodium salt of Oethoxycarbonylthiarnine is added(p-tolylthio)-thiocarbonyl chloride (6.7 parts by weight) at -30 -20 C,and the mixture is stirred for 1.5 hours. Working up in a similar mannerto the procedure 1a of Example 1., the crude product is recrystallizedfrom ethyl acetate-ether to giveO-ethoxycarbonyl-S-(p-tolylthio)-thiocarbonylthiamine (12 parts byweight), m.p. 109 111 C. Anal. Calcd. for C H ON,S C, 53.05; H, 5.42; N,10.76; S, 18.47. Found: C, 52.66; H, 5.31; N, 10.74; S, 18.21. IR cm:1738, 1670,1254, 1040, 1010.

Procedure 1b SEthoxycarbonylthiamine (17.4 parts by weight) is added to5 percent aqueous sodium hydroxide solution (40 parts by weight) and themixture is stirred at room temperatures for 15 minutes. To the mixtureis added a solution of carbon disulfide (11.4 parts by weight) indimethylformamide (200 parts by volume), and the resultant mixture isstirred for 15 minutes under ice-cooling. To the mixture is addeddropwise a solution of di-(p-tolyl)iodonium iodide (23.5 parts byweight) in dimethylformamide (200 parts by volume) at 0 4 C, and themixture is stirred at the same temperature for 7 hours. Working up on asimilar manner to the procedure 1b of EXAMPLE 1., there is obtainedO-ethoxycarbonyl-S-(p-tolylthio)- thiocarbonylthiamine (1.6 parts byweight), which is identical with that produced by the procedure la ofthis Example. Procedure 2a To a suspension of S-sodium salt ofthiol-type thiamine (5.1 parts by weight) in anhydrous ethanol (35 partsby volume) is added dropwise p-tolylthiothiocarbonyl chloride (2.5 partsby weight) below 10 C, and the mixture is allowed to stand at the sametemperature for 2 hours. The temperature is gradually elevated to roomtemperature, and the precipitates are collected by filtration. Afterwashing with water, recrystallization from ethanol givesS-(p-tolylthio)-thiocarbonylthiamine (3.2 parts by weight), m.p. 117 118C (decompd). Anal. Calcd. for C H O N S C, 53.53; H, 5.39; N, 12.49; S,21.44. Found: C, 53.89; H, 5.22; N, 12.47; S, 2114.

To a solution of S-(p-tolylthio)-thiocarbonylthiamine (3.0 parts byweight) in chloroform (50 parts by volume) is added dropwise anothersolution of phosgene (1.0 part by weight) in toluene (2 parts byvolume), and the resultant mixture is stirred at room temperature (10 30C) for 3 hours. After removal of the solvent under reduced pressure, theresidue is added with ethanol (10 parts by volume), and the mixture isheated at 50 C for 1 hour. Evaporating under reduced pressure, theresidue is extracted with chloroform, the extract is washed with water,sodium hydrogen carbonate and water successively, dried with anhydroussodium sulfate and evaporated. The residue is recrystallized from ethylacetateether to giveO-ethoxycarbonyl-S-(p-tolylthio)-thiocarbonylthiamine (3.0 parts byweight), which is identical with that produced by the procedure 1a ofthis EXAMPLE.

Procedure 2b To a suspension of S-sodium salt of thiol-type thiamine(containing 2 molar equivalents of sodium chloride) (22.5 parts byweight) in dimethylformamide (200 parts by volume) is added carbondisulfide (11.4 parts by weight), and the mixture is stirred at 0 4 Cfor 10 minutes. Then, to the mixture is added dropwise a solution ofdi-(p-tolyl)-iodonium iodide (21.8 parts by weight) in dimethylformamide(200 parts by volume) at 0 -4 C, and the mixture is stirred at the sametemperature for 4 hours. After dilution with water, the mixture isextracted with chloroform, the extract is washed with water, dried withanhydrous sodium sulfate, and evaporated. The residue is purified bysilica-gel chromatography, and then recrystallized from chloroform togive S-(p-tolylthio)-thiocarbonyl thiamine (13.5 parts by weight), whichis identical with that produced in the procedure 2a of this Example.

The intermediary product is subsequently treated with phosgene andethanol in the same manner as described in the procedure 2a of thisexample to give O-ethoxycarbonyl-S-(ptolylthio)-thiocarbonylthiamine(12.0 parts by weight), which is identical with that produced in theprocedure (1a) of this example.

EXAMPLE 3 Preparation of O-Ethoxycarbonyl-S-(3,5-xylythioThiocarbonylthiamine Procedure la To a suspension ofS-ethoxycaronbylthiamine (17.7 parts by weight) in anhydrous ethanol(150 parts by volume) is added dropwise a solution of metallic sodium(1.15 parts by weight) in anhydrous ethanol (100 parts by volume) at 10-15 C. The mixture is warmed to 20 C and allowed to stand at the sametemperature for 5 minutes. To the thus prepared solution of S-sodiumsalt of O-ethoxycarbonylthiamine is added 3,5-xylythiothiocarbonylchloride (10.8 parts by weight) at 30 20 C, and the mixture is stirredfor 1.5 hours. Then, the reaction mixture is adjusted to pH 2.0 with 20percent ethanolic hydrogen chloride, evaporated under reduced pressure,and the residue is extracted with chloroform. The extract is washed withwater, sodium hydrogen carbonate solution and water successively, driedwith anhydrous sodium sulfate and evaporated. The residue isrecrystallized from ethyl acetate-ether to giveO-ethoxycarbonyl-S-(3,5-xylylthio)- thiocarbonylthiamine (1.5 parts byweight), m.p. 94 95 C. Anal. Calcd. for C H O N S C, 53.92; H, 5.65; N,10.48; S,

17.98. Found: c, 54.09; H, 5.52; N, 10.32; 5, 17.95. [R vgg;

EXAMPLE 4.

Procedure in To a suspension of S-ethoxycarbonylthiamine (44.4 parts byweight) in anhydrous ethanol (600 parts by volume) is added dropwise asolution of metallic sodium (28.8 parts by weight) in anhydrous ethanol(200 parts by volume) at C. The mixture is warmed to C and allowed tostand at the same temperature for 5 minutes. To the thus preparedsolution of S- sodium salt of O-ethoxycarbonylthiamine is added 0-bromophenylthiothiocarbonyl chloride (32.5 parts by weight) at -40 -30C, and the mixture is stirred at 1.5 hours. The reaction mixture (pH8.0) is evaporated under reduced pressure and the residue is extractedwith chloroform. The extract is washed with water, dried with anhydroussodium sulfate and evaporated. The residue is recrystallized fromethanol to give O-ethoxycarbonyl-S-(o-bromophenylthio)-thiocarbonylthiamine (51.5 parts by weight), m.p.145 -148 C (decompd). Anal. Calcd. for C H O N S Br: C, 45.12; H, 4.30;N, 9.57; S, 16.43. Found: C, 45.29; H, 4.40; N, 9.34; S, 16.27. IR vgjcm: 1747, 1046. Procedure 1b O-Ethoxycarbonyl-S-( o-bromophenylthio)-thiocarbonylthiamine is produced in a similar manner to the procedure1b of Example 1, but using di-O-bromophenyl)-iodonium iodide in place ofdiphenyliodonium iodide. Procedure 2a O-Ethoxycarbonyl-S-(O-bromophenylthio )-thiocarbonylthiamine is produced from S-sodium saltof thiol-type thiamine via S-(O-bromophenylthio)-thiocarbonylthiamine,m.p. 181 183 C. (decompd), in a similar manner to the procedure 2a ofExample 1, but using O-bromophenylthiothiocarbonyl chloride in place ofphenylthiothiocarbonyl chloride. Procedure 2b OEthoxycarbonyl-S-(O-bromophenylthio )-thiocarbonylthiamine is produced from S-sodium saltof thiol-type thiamine via S-(O-bromophenylthio)-thiocarbonyl-thiarninein a similar manner to the procedure 2): of Example 1, but usingdi-(O-bromophenyl)-iodonium iodide in place of diphenyliodonium iodide.

EXAMPLE 5.

Preparation of O-Ethoxycarbonyl-S-( P-MethoxyphenylthioThiocarbonylthiamine Procedure la To a solution of metallic sodium (3.16parts by weight) in anhydrous ethanol (600 parts by volume) is added at10 C S- ethoxycarbonylthiamine (48.7 parts by weight), and the mixtureis stirred at 20 C for 5 minutes. To the thus prepared solution ofS-sodium salt of O-ethoxycarbonylthiamine is addedP-methoxyphenylthiothiocarbonyl chloride parts by weight) at -30 20 C,and the mixture is stirred at the same temperature for 1.5 hours. Afterremoval of ethanol, the residue is extracted with chloroform. Theextract is washed with water, dried with anhydrous sodium sulfate, andevaporated. The residue is purified by silica-gel chromatography, andfractions eluted with acetone containing O-ethoxycarbonyl-S-(P-methyoxyphenylthio )-thiocarbonylthiamine are collected. Afterevaporation, the residue is treated with a saturated ethereal solutionof oxalic acid and the precipitated crystals are collected byfiltration. Recrystallization from ethanol gives O-ethoxycarbonylS-(P-methoxyphenylthio)- thiocarbonylthiamine oxalate (40 parts byweight), m.p. 133 -13S C. Anal. Calcd. for C H O N S C, 47.91; H, 4.82;N, 8.94; S, 15.35. Found: C, 47.77; H, 4.86; N, 8.95; S, 14.94. [R Eggcm; 1730, 1055.

Procedure 1b O-Ethoxycarbonyl-S-( P-methoxyphenylthio)-thiocarbonylthiamine is produced in a similar manner to the procedure1b of Example 1, but using di-(P-methoxyphenyl)-iodonium iodide in placeof diphenyliodonium iodide. Procedure 2a O-Ethoxycarbonyl-S-(P-methoxyphenylthio )-thiocarbonuylthiamine is produced from S-sodiumsalt of thiol-type thiamine viaS-(P-methoxyphenylthio)-thiocarbonylthiamine in a similar manner to theprocedure 2a of Example 1, using P- methoxyphenylthiothiocarbonylchloride in place of phenylthiothiocarbonyl chloride.

Procedure 2bO-EthoxycarbonylS-(p-methoxyphenylthio)-thiocarbonylthiamine is producedfrom S-sodium salt of thiol-type thiamine viaS-(p-methoxyphenylthio)-thiocarbonylthiamine in a similar manner to theprocedure 2b of Example 1, but using di-( p-methoxyphenyl)-iodoniumiodide in place of diphenyliodonium iodide.

What is claimed is:

1. A member selected from the group consisting of the compounds of theformula:

wherein R and R each is a member selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy and halogen and R" is lower alkyl.

2. An O (lower)-alkoxycarbonyl-S-phenylthiothiocarbonylthiamine.

3. AnO-(lower)-alkoxycarbonyl-S-{(lower)-alkylphenylthio]-thiocarbonylthiamirie.

4. An O-(lower)-alkoxycarbonyl-S-[di-(lower)-alkylphenylthio]-thiocarbonylthiamine.

5. AnO-(lower)-alkoxycarbonyl-S-[(lower)-alkoxyphenylthio]-thiocarbonylthiamine.

6. An O-(lower)-alkoxycarbonyl-S-(halogenophenylthio)-thiocarbonylthiamine.

7. A compound according to claim 1 or 2, namelyO-ethoxycarbonyl-S-phenylthiothiocarbonylthiamine.

8. A compound according to claim 1 or 3, namely O-ethoxycarbonyl-S-(p-tolylthio)-thiocarbonylthiamine.

9. A compound according to claim 1 or 4, namelyO-ethoxycarbonyl-S-(3,5-xylylthio )-thioca.rbonylthiamine.

10. A compound according to claim 1 or 5, namely 0-ethoxycarbonyl-S(p-methoxyphenylthi0)-thiocarbonylthiamine.

11. A compound according to claim 1 or 6, namely 0- ethoxycarbonyl-S-(o-bromophenylthio )-thiocarbonylthiamine.

2. An O-(lower)-alkoxycarbonyl-S-phenylthiothiocarbonylthiamine.
 3. AnO-(lower)-alkoxycarbonyl-S-((lower)-alkylphenylthio)-thiocarbonylthiamine.4. An O-(lower)-alkoxycarbonyl-S-(di-(lower)-alkylphenylthio)-thiocarbonylthiamine.
 5. AnO-(lower)-alkoxycarbonyl-S-((lower)-alkoxyphenylthio)-thiocarbonylthiamine.6. AnO-(lower)-alKoxycarbonyl-S-(halogenophenylthio)-thiocarbonylthiamine. 7.A compound according to claim 1 or 2, namelyO-ethoxycarbonyl-S-phenylthiothiocarbonylthiamine.
 8. A compoundaccording to claim 1 or 3, namelyO-ethoxycarbonyl-S-(p-tolylthio)-thiocarbonylthiamine.
 9. A compoundaccording to claim 1 or 4, namelyO-ethoxycarbonyl-S-(3,5-xylylthio)-thiocarbonylthiamine.
 10. A compoundaccording to claim 1 or 5, namelyO-ethoxycarbonyl-S-(p-methoxyphenylthio)-thiocarbonylthiamine.
 11. Acompound according to claim 1 or 6, namelyO-ethoxycarbonyl-S-(o-bromophenylthio)-thiocarbonylthiamine.